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DEATH DUE TO CHD IN THE USA IN 1986

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1 DEATH DUE TO CHD IN THE USA IN 1986
BUSH, ANN NY ACAD SCI,1990

2 PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND LIPID RISK FACTORS IN 45 TO 55 YEARS OLD WOMEN
Pre-Menopause Menopause P (n = 1537) (n = 2456) age (years) ± ± 3.0 < 0.001 BMI (kg/m2) ± ± 4.5 < 0.001 cholesterol (mg/dL) 221 ± ± 41 < 0.001 triglycerides (mg/dL)* < 0.001 LDL-C (mg/dL) ± ± 38 < 0.001 HDL-C (mg/dL) ± ± 16 n.s. chol./HDL-C ratio ± ± < 0.001 *: geometric mean, n.s.: not significant

3 PROCAM (MÜNSTER HEART STUDY): MENOPAUSE AND HEMOSTATIC RISK FACTORS IN 45 TO 55 YEARS OLD WOMEN
Pre-Menopause Menopause P (n = 229) (n = 307) fibrinogen (mg/dL) 265 ± ± 56 < 0.001 D-dimer (mg/l)* n.s. factor VIIc (mg/dL) ± ± 34 < 0.001 protein C (%) ± ± 24 < 0.001 plasminogen (%) ± ± 14 < 0.05 PAI-1 (U/l) * < 0.05 vWF (%) ± ± n.s. CRP (mg/dL)* < 0.05 *: geometric mean

4 MAJOR RISK FACTORS FOR CHD
AGE > 45 Y MALES AND > 55 Y FEMALES Family history of MI or sudden death: < 55 males < 65 females Cigarettes smoke Elevated blood pressure HDL-C < 35 mg/dL Diabetes mellitus HDL-C > 60 mg/dL NATIONAL CHOLESTEROL EDUCATION PROGRAM. CIRCULATION 1994;89:

5 POSTMENOPAUSAL ESTROGEN/PROGESTIN INTERVENTIONS TRIAL (PEPI)
875 HEALTHY POST-MENOPAUSAL WOMEN AGE 45-64 PARALLEL INTERVENTION GROUPS: Placebo CEE mg/d CEE mg/d + MPA 10 mg/d x 12 d/mo CEE mg/d + MPA 2.5 mg/d CEE mg/d + MP 200 mg/d x 12 d/mo ENDPOINTS: HDL-C Systolic blood pressure Fibrinogen Insulin Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial was a prospective, randomized 3-year study that compared the effects of unopposed conjugated equine estrogen (CEE), estrogen plus either cyclic or consecutive medroxyprogesterone acetate (MPA), estrogen plus cyclic micronized progesterone (MP), and placebo on selected endpoints related to CHD risk: HDL-C, systolic blood pressure, fibrinogen, and insulin. Reference: Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda JAMA 1995;273:199

6 SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups
PEPI TRIAL RESULTS LIPOPROTEINS: HDL-C increased in all active treatments (Greatest with CEE and CEE + MP) LDL-C decreased equally in all treatment groups Triglycerides increased equally in all treatment groups SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups INSULIN: no difference in fasting or 2-hour insulin among all treatment groups FIBRINOGEN: no difference among active treatment groups Slide 5. PEPI Trial results The greatest increases in HDL-C were with estrogen alone (4.1 mg/dl) or with estrogen plus MP (5.6 mg/dl); HDL-C also increased with estrogen plus MPA (1.2–1.6 mg/dl), but decreased with placebo (–1.2 mg/dl). LDL-C decreased in all active treatment groups, and triglyceride increased as is typical with estrogen. Systolic blood pressure increased and postchallenge insulin decreased, but neither was significantly different among treatment groups. Fibrinogen increased significantly more with placebo, but differences among active treatment groups were not statistically significant. Although unopposed estrogen produced the greatest HDL-C increases, women in this treatment group with a uterus had increased risk for endometrial hyperplasia, which was not seen with the combination regimens. Reference: Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda JAMA 1995;273:199

7 EFFECTS OF ORAL ESTROGENS ON SERUM LIPOPROTEINS IN POSMENOPAUSAL WOMEN
50 100 150 200 250 mg/dL Total C LDL-C HDL-C TGL Run-in Baseline 3 months Oral Transdermal -5% -15% +37% BRANCHI A., 1998

8 SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups
PEPI Trial Results LIPOPROTEINS: HDL-C increased in all active treatments (Greatest with CEE and CEE + MP) LDL-C decreased equally in all treatment groups Triglycerides increased equally in all treatment groups SYSTOLIC BLOOD PRESSURE: increased similarly in all treatment groups INSULIN: No difference in fasting or 2-hour insulin among all treatment groups FIBRINOGEN: No difference among active treatment groups Slide 5. PEPI Trial results The greatest increases in HDL-C were with estrogen alone (4.1 mg/dl) or with estrogen plus MP (5.6 mg/dl); HDL-C also increased with estrogen plus MPA (1.2–1.6 mg/dl), but decreased with placebo (–1.2 mg/dl). LDL-C decreased in all active treatment groups, and triglyceride increased as is typical with estrogen. Systolic blood pressure increased and postchallenge insulin decreased, but neither was significantly different among treatment groups. Fibrinogen increased significantly more with placebo, but differences among active treatment groups were not statistically significant. Although unopposed estrogen produced the greatest HDL-C increases, women in this treatment group with a uterus had increased risk for endometrial hyperplasia, which was not seen with the combination regimens. Reference: Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1995;273: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda JAMA 1995;273:199

9 ANTIATHEROGENE PROPERTILE OF ESTROGENS
Reduced proliferation of SMC and neo intima formation Reduced production of collagen and elastin Modulation of vasomotor response Increased coronary responsed to vasodilatory stimuli Increased prostacyclyn production by SMC Reduction of plasma homocysteine levels

10 RELATIVE RISK AND 95% CI FROM STUDIES OF ESTROGEN USE TO PREVENT CHD
Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda STAMPFER, NEJM, 1991

11 THE NURSES HEALTH STUDY: CHD RISK AND POSTMENOPAUSAL ESTROGEN + PROGESTIN USE
59,337 women, age 30-55, followed for 16 years Relative risk for CHD events in current estrogen users was 0.60, and current estrogen + progestin users was 0.39 Length of HRT did not change risk reduction Estrogen doses of 0.3 and mg had the greatest benefit Women years old had as much benefit as younger women The Nurses Health Study: CHD risk and postmenopausal estrogen + progestin use Observational epidemiological data from the Nurses' Health Study indicated that women who took estrogen had a lower risk for CHD than women who did not take estrogen. On the basis of this large study, which followed up almost 60,000 women for 16 years, hormone-replacement therapy appeared to be an appropriate means of preventing CHD in postmenopausal women, with benefit also seen in women who did not begin estrogen immediately after menopause. Reference: Grodstein F, Stampfer MJ, Manson JAE, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med 1996;335: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda NEJM 1996;335:453

12 ESTROGEN REPLACEMENT IN POSTMENOPAUSAL WOMEN: NCEP RECOMMENDATIONS
Observational information suggests lower CHD risk in women on HRT Experimental data suggests estrogen has beneficial effects on endothelial function Oral estrogen can lower LDL-C and increase HDL-C NCEP recommends that estrogen replacement can be used as alternative or adjunctive treatment to manage hypercholesterolemia in postmenopausal women. Slide 3. Estrogen replacement in postmenopausal women: NCEP recommendations In addition to observational epidemiological data suggesting that estrogen reduces CHD risk, experimental data suggest that estrogen improves endothelial function through promoting the production of nitric oxide and therefore improving vascular reactivity. Oral administration of estrogen favorably affects lipid metabolism, decreasing LDL-C, increasing HDL-C, and decreasing lipoprotein(a) (Lp(a)). On the basis of this combined evidence, the National Cholesterol Education Program (NCEP) guidelines recommend estrogen-replacement therapy as an alternative to lipid-lowering drug therapy in postmenopausal women. Reference: National Cholesterol Education Program. Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994 Mar;89(3): Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda

13 HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS)
Randomized, placebo-controlled trial of E/P therapy vs. placebo in 2,763 women with CHD; average age 67 years Treatment was mg CEE* mg medroxyprogesterone daily for 4 years Primary endpoint: nonfatal MI and CHD death Secondary endpoints: CABG, PTCA, unstable angina, CHF, PVD, TIA *CEE = conjugated equine estrogen; Slide 11. Heart and Estrogen/Progestin Replacement Study (HERS): secondary prevention of CHD in women HERS examined the observational association between estrogen replacement and CHD risk reduction in a randomized prospective trial of estrogen plus MPA at fixed dosages in women with CHD. Reference: Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda JAMA 1998;280:

14 Mean % change from baseline
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) CHANGES IN LIPID LEVELS AT 1 YEAR 15 10* 10 8* 5 2 Mean % change from baseline -2 -5 -3 Heart and Estrogen/Progestin Replacement Study (HERS) Changes in Lipid Levels at 1 Year By the end of the first year of treatment in the Heart and Estrogen/Progestin Replacement Study (HERS), mean low-density lipoprotein cholesterol (LDL-C) levels had decreased by 14% from baseline (to 125 mg/dL) in the hormone-treated group versus a 3% decrease (to 140 mg/dL) in the placebo group (P < 0.001). During the same period, mean high-density lipoprotein cholesterol (HDL-C) levels had increased by 8% (to 54 mg/dL) in the hormone-treated-group and had decreased by 2% (to 49 mg/dL) in the placebo group (P < 0.001). Mean triglyceride (TG) levels had increased by 10% (to 181 mg/dL) in the hormone-treated group versus a 2% increase (to 170 mg/dL) in the placebo group (P < 0.001). Reference: Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613. Placebo Estrogen/progestin -10 -15 -14* -20 LDL-C HDL-C TG Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda *P < 0.001 HULLEY S ET AL. JAMA 1998;280:605–613

15 THE HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) INCIDENCE OF CHD EVENTS IN TREATMENT AND PLACEBO GROUPS Placebo (n=1383) Estrogen/Progestin (N=1380) CHD Death + Nonfatal MI CHD Death Coronary Revascularisation or Unstable Angina Incidence (%) RH = 0.99 p = 0.91 p = 0.46 RH = 1.24 p = 0.23 RH = 0.88 p = 0.15 Follow-up (years) HULLEY ET AL. JAMA 1998; 280:

16 Follow-up, y (No. at risk)
HEART AND ESTROGEN/PROGESTIN REPLACEMENT STUDY (HERS) CUMULATIVE INCIDENCE OF PRIMARY CHD EVENTS 15 10 5 (2,763) 1 (2,631) 2 (2,506) 3 (2,392) 4 (1,435) (113) Incidence (%) Follow-up, y (No. at risk) Estrogen/progestin Placebo Heart and Estrogen/Progestin Replacement Study (HERS) Cumulative Incidence of Primary CHD Events In the Heart and Estrogen/Progestin Replacement Study (HERS), primary coronary heart disease (CHD) events occurred in 172 women (12%) in the hormone-treated group (33.1/1,000 women per year) and in 176 women (13%) in the placebo group (33.6/1,000 women per year) (relative hazard [RH]: 0.99). This slide presents the survival curves for the primary CHD outcome (cumulative incidence of primary CHD events). The numbers in parentheses represent the number of women observed at each year of follow-up and still free of an event. The log rank P value for primary CHD events was Thus, in this population of postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) did not reduce the incidence of primary CHD events during an average of 4.1 years of follow-up. Moreover, in addition to providing no overall cardiovascular benefit, treatment with CEE + MPA increased the risk of venous thromboembolic events and gall-bladder disease (data not shown). The investigators could not recommend starting this combination in postmenopausal women for secondary prevention of CHD. However, they noted that women who have been receiving such treatment for a number of years and who have not experienced an adverse event may continue treatment and may derive a benefit. Reference: Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–613. Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda Hulley S et al. JAMA 1998;280:605–613

17 SIDE-EFFECTS IN HERS STUDY
confirmed venous thrombosis deep vein thrombosis pulmonary embolus fatal pulmonary Embolus gallbladder disease oestrogen/ progestin (n=1380) 34 25 11 2 84 placebo (n=1383) 12 8 4 62 relative risk 2.3 3.1 2.8 - 1.4 P value 0.002 0.004 0.08 - 0.05 HULLEY ET AL. JAMA 1998; 280:

18 HERS RESULTS No statistically significant difference between HRT
and placebo in both primary and secondary endpoints after 4 years. Within first year, greater incidence in CHD events in HRT group. In years 3 and 4, lower CHD events in HRT group compared to placebo. HRT lowered LDL 11% and increased HDL 10% compared to placebo. Approximately 50% of randomized women were on lipid-lowering drugs. Higher incidence of VTE and cholelithiasis in HRT group. Slide 13. HERS results: summary On the basis of the HERS results, the investigators concluded that a woman with CHD who is already on hormone-replacement therapy should not discontinue therapy, because hormone treatment reduced CHD risk at later time points during the study. However, with the lack of overall CHD benefit combined with a trend toward increased CHD risk, the authors did not recommend initiating hormone-replacement therapy as secondary prevention in a woman not currently on therapy. Reference: Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280: Società Italiana per lo Studio dell’ Aterosclerosi Sez. Regionale Lombarda JAMA 1998;280:

19 CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II)
The higher risk of developing CHD in HERS was in the first two years of therapy. A decline occured between year 3 and 5. HERS II was designed to verify whether the tendency to a reduction of CHD in HERS persisted in a longer follow up. The HERS II study recruited women (average 67 yearsof age) who gave their informed consent to continue therapy with the active drug or placebo. GRADY ET AL., JAMA 2002

20 CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II)
JAMA, 2002

21 NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 1
JAMA, 2002

22 NON CHD OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY (HERS II) 2
JAMA, 2002

23 RISK AND BENEFITS OF ESTROGEN PLUS PROGESTIN IN HEALTHY POSTMENOPAUSAL WOMEN Principal Results from the Women’s Health Initiative Randomized Controlled Trial A randomized controlled primary prevention trial (planned duration 8.5 years) in which 16,608 postmenopausal women aged years with an intact uterus at baseline were recruited by 40 US clinical centers in Participants received conjugated equine estrogens, mg/d, plus medroxyprogesterone acetate, 2.5 mg/d or placebo JAMA, 2002

24 PROFILE OF THE ESTROGEN+PROGESTIN COMPONENT OF THE WOMEN’S HEALTH INITIATIVE
373,092 women initiated screening 18,845 provided consent and reported no isterectomy 16,608 randomized 8,506 assigned to Estrogen+Progestin 8,102 assigned to placebo Status on April 30, 2002 7,968 alive 307 unknown vital status 231 deceased 7,608 alive 276 unknown vital status 218 deceased

25 WHI: CLINICAL OUTCOMES 1
JAMA, 2002

26 WHI: CLINICAL OUTCOMES 2
JAMA, 2002

27 WHI: CLINICAL OUTCOMES 3
JAMA, 2002

28 WHI: CAUSE OF DEATH JAMA, 2002

29 CONCLUSIONS Overall health risk exceeded benefits from use of combined estrogen+progestin for an average 5.2 year follow-up among healthy postmenopausal women Risk for CHD was largely limited to the 1° year of therapy, whereas risk for Stroke and Venous Thromboembolism continued throughout the 5 years of therapy and may reflect prothrombotic and proinflammatory effects of progestins Risk for breast cancer was associated with the duration of treatment The risk-benefit profile of combined HRT is not consistent with the requirements for primary prevention of chronic diseases

30 MENOPAUSAL HORMONE REPLACEMENT THERAPY AND RISK OF OVARIAN CANCER
Study Design: cohort study on post menopausas women Aim: to address whether the estrogen + progestin treatment could modify the risk of developping ovary cancer LACEY, JAMA 2002

31 HORMONAL REPLACEMENT THERAPY AND OVARIAN CANCER
No therapy Estrogens Estrogens+ Progestins Years-person 42.400 N° of ovarian cancer 120 116 18 Relative Risk 1.0 1.6 ( ) 1.1 ( ) LACEY, JAMA 2002

32 INTERVENTION STUDIES AIMED AT THE PREVENTION OF CORONARY HEART DISEASE (SUBGROUPS OF WOMEN)
4S: The Lancet 1994;344: Care: Sacks FM et al. N Engl J Med 1996;335: AFCAPS/TexCAPS: Downs JR et al. JAMA 1998;279:

33 SIMVASTATIN: SECONDARY ENDPOINT VASCULAR EVENTS BY AGE AND GENDER
STATIN worse VASCULAR EVENTS BY AGE AND GENDER Relative Risk IC 95% SIMVA PLACEBO GROUPS (10269) (10267) SIMVA better Placebo better AGE (YEAR) Het  2 3 = 4.4 < 65 838 1093 516 677 70-74 550 628 >75 138 208 GENDER 1 = 0.4 Male 1676 2148 Female 366 458 All patients 2042 2606 (19.9%) (25.4%) 24% SE 2.6 (2P< ) 0.4 0.6 0.8 1.0 1.2 1.4

34 HORMONAL REPLACEMENT THERAPY (WHEN TO BE USED)
Menopausal symptoms (vasomotor, urogenital or vaginal atrophy, mood disturbance) High risk of osteoporosis Early menopause


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